1. Technical Field
The present invention generally relates to amorphous and crystalline forms of aprepitant and processes for their preparation.
2. Description of Related Art
Aprepitant, also known as 5-[[(2R,3S)-2-[(1R-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one, is represented by the structure of Formula I:
Aprepitant is a selective high-affinity antagonist of human substance P/neurokinin 1 (NK1) receptors. Aprepitant has little or no affinity for serotonin (5-HT3), dopamine and corticosteroid receptors, which are the targets of some therapies for chemotherapy-induced nausea and vomiting (CINV). Aprepitant, in combination with other antiemetic agents, is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy, including high-dose cisplatin and is commercially sold under the trade name Emend®. See, e.g., Physician's Desk Reference, “Emend,” 60th Edition, pp. 1944-1949 (2005).
U.S. Pat. No. 5,719,147 discloses aprepitant and a process for its preparation.
U.S. Pat. No. 6,096,742 discloses a polymorphic form of the compound 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine characterized by an X-ray powder diffraction pattern with key reflections at approximately: 12.0, 15.3, 16.6, 17.0, 17.6, 19.4, 20.0, 21.9, 23.6, 23.8, and 24.8.degree. (2 theta) which is substantially free of a polymorphic form of the compound 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-S)-(4-fluoro)-phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine characterized by an X-ray powder diffraction pattern with key reflections at approximately: 12.6, 16.7, 17.1, 17.2, 18.0, 20.1, 20.6, 21.1, 22.8, 23.9, and 24.8.degree. (2 theta).
The present invention relates to the solid state physical properties of aprepitant. These properties can be influenced by controlling the conditions under which aprepitant is obtained in solid form. Solid state physical properties affect the ease with which the material is handled during processing into a pharmaceutical product such as a tablet or capsule formulation. The physical properties can also impact the type of excipients, for instance, to add to an aprepitant formulation. Furthermore, the solid state physical property of a pharmaceutical compound is important to its dissolution in aqueous fluid or even in a patient's stomach fluid, which have therapeutic consequences. The rate of dissolution is also a consideration in liquid forms of medicine as well. The solid state form of a compound may also affect its storage conditions.
These practical physical characteristics are influenced by the particular form of a substance. For example, polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different x-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable solubility profiles. The amorphous and crystalline forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry.
Generally, amorphous materials do not exhibit the three dimensional long-range order ordinarily found in crystalline material and are structurally more similar to liquids where the arrangement of molecules is random. Additionally, amorphous solids are substantially not crystalline and therefore do not give a definitive x-ray diffraction pattern (XPD). They also do not give rise to a melting point and tend to liquefy at some point beyond the glass transition point.
The present invention relates to an amorphous form and polymorphic mixtures of aprepitant. Moreover the present invention relates to additional processes for preparation of amorphous aprepitant and polymorphic mixtures of aprepitant.